Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) for the treatment of neurodegenerative diseases

Abstract

Small molecule inhibitors of neutral sphingomyelinase 2 (nSMase2) and their use for treating neurodegenerative diseases, such as, neurodegenerative diseases associated with high levels of ceramide, including, but not limited to Alzheimer's disease (AD), HIV-associated neurocognitive disorder (HAND), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), and, in other aspects, for treating cancer, are provided.

That which is claimed: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         R 3  is selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxyl, substituted or unsubstituted thioalkyl, substituted or unsubstituted aryl, and halogen; 
         R 4  is selected from the group consisting of H, substituted or unsubstituted alkyl, and substituted or unsubstituted aryl; 
         R 5  is selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring; 
         R 6  is selected from the group consisting of H or substituted or unsubstituted C 1-6  alkyl; and 
         R 7  is selected from the group consisting of —C(═O)—(CR y R z ) m —R 8 , —C(═O)—(CR y R z ) m —O—R 8 , —C(═O)—O—(CR y R z ) m —R 8 , and —S(═O) 2 —R 9 , wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R y  and R z  are each independently H, alkoxyl, or halogen, R 8  and R 9  are each independently selected from the group consisting of substituted or unsubstituted alkyl, —CF 3 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR 10 R 11 , wherein R 10  and R 11  are each independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, and substituted or unsubstituted aryl; and 
         pharmaceutically acceptable salts thereof. 
       
     
     
       2. The compound of  claim 1 , wherein the compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       wherein:
 p is an integer selected from the group consisting of 0, 1, 2, 3, 4, and 5; 
 each R 12  is independently selected from the group consisting of substituted or unsubstituted alkyl, hydroxyl, alkoxyl, halogen, cyano, amino, —CF 3 , —O—CF 3 , substituted or unsubstituted cycloheteroalkyl, —NR 13 (C═O)R 14 , —S(═O) 2 —R 15 , —S(═O) 2 —NR 15 R 16 , —C(═O)—R 17 , —C(═O)—O—R 18 , and —C(═O)—NR 19 R 20 , wherein R 13  is selected from the group consisting of H or substituted or unsubstituted C 1-6  alkyl, R 14  is substituted or unsubstituted C 1-6  alkyl or —O—R 21 , and R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21  are each independently H or substituted or unsubstituted C 1-6  alkyl. 
 
     
     
       3. The compound of  claim 2 , wherein R 6  is H and R 7  is —C(═O)—(CR y R z ) m —R 8 , wherein m is 0 and R 8  is C 1-6  alkyl. 
     
     
       4. The compound of  claim 3 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       5. The compound of  claim 2 , wherein R 6  is H and R 7  is selected from the group consisting of —C(═O)—(CR y R z ) m —R 8 , —C(═O)—(CR y R z ) m —O—R 8 , —C(═O)—O—(CR y R z ) m —R 8 , wherein each m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6, R y  and R z  are each independently H, alkoxyl, or halogen, R 8  is selected from the group consisting of substituted or unsubstituted alkyl, —CF 3 , substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloheteroaryl, substituted or unsubstituted multicyclic aryl or heteroaryl ring, and NR 10 R 11 , wherein R 10  and R 11  are each independently selected from the group consisting of H, substituted or unsubstituted C 1-6  alkyl, and substituted or unsubstituted aryl. 
     
     
       6. The compound of  claim 5 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 2 , wherein R 6  is H and R 7  is —S(═O) 2 —R 9 . 
     
     
       8. The compound of  claim 5 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       9. The compound of  claim 1 , wherein R 5  is selected from the group consisting of H, halogen, and substituted or unsubstituted alkyl. 
     
     
       10. The compound of  claim 9 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       11. The compound of  claim 1 , wherein R 5  is a substituted or unsubstituted multicyclic aryl or multicyclic heteroaryl ring. 
     
     
       12. The compound of  claim 11 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       13. The compound of  claim 1 , wherein R 5  is a substituted or unsubstituted heteroaryl. 
     
     
       14. The compound of  claim 13 , wherein the compound of formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       15. A method for treating a subject afflicted with Alzheimer's disease, the method comprising administering to a subject in need of treatment thereof an effective amount of compound of  claim 1 . 
     
     
       16. The method of  claim 15 , wherein the administration of an effective amount of a compound of formula (I) to the subject decreases a neutral sphingomyelinase 2 (nSMase2) activity or expression or decreases a level of ceramide in the subject. 
     
     
       17. A method for inhibiting neutral sphingomyelinase 2 (nSMase2), the method comprising administering to a subject, cell, or tissue an amount of a compound of  claim 1 .